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Mavaddat, Nasim. "Risk modelling in BRCA1 and BRCA2 mutation carriers". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610839.
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Ewald, Ingrid Petroni. "Caracterização de um grupo de pacientes em risco para câncer de mama e ovário hereditários quanto a presença e frequência de rearranjos gênicos em BRCA". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/53154.
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O câncer de mama é uma das neoplasias malignas mais comuns que afetam mulheres de todo o mundo. No Brasil, o Estado do Rio Grande do Sul tem índices de incidência e mortalidade por câncer de mama que situam-se entre os maiores do país. Aproximadamente 5-10% dos diagnósticos são causados por mutações germinativas em genes de predisposição entre os quais estão BRCA1 e BRCA2, associados à Síndrome de Câncer de mama e Ovário Hereditários (Hereditary Breast and Ovarian Cancer Syndrome ou HBOC, OMIM #114480).A identificação dos casos hereditários de câncer de mama é importante porque indivíduos afetados apresentam risco cumulativo vital muito superior ao da população para o desenvolvimento de câncer, porque familiares de um afetado podem estar igualmente em risco porque há medidas de rastreamento intensivo e intervenções preventivas que podem diminuir significativamente o risco de câncer em portadores de mutação. O diagnóstico molecular da síndrome HBOC é laborioso e caro devido à heterogeneidade molecular da doença. Famílias que apresentam características indicativas de uma síndrome de predisposição ao câncer de mama e ovário hereditários, mas que são negativas para mutações pontuais em BRCA1/2 vêm sendo testadas para grandes rearranjos visto que essas anormalidades têm sido consideradas como respondendo por, no mínimo, 10% do todos os casos HBOC com mutação identificável, incluindo grandes deleções ou duplicações. Um estudo recente de Portugal, demonstrou que um rearranjo fundador no exon 3 de BRCA2 ocorre em por 8% das famílias HBOC do Norte do país. Os objetivos deste trabalho incluíram a verificação da freqüência e caracterização de rearranjos gênicos nos genes BRCA1 e BRCA2, incluindo a mutação fundadora c.156_157insAlu no exon 3 de BRCA2 em famílias brasileiras dealto risco para a síndrome HBOC. Em um grupo de 145 indivíduos em risco nãorelacionados rastreados para a mutação fundadorac.156_157insAlu no exon 3 de BRCA2 foram encontrados 3 portadores da mutação (prevalência de 2%). Em um grupo de 145 indivíduos de risco não-relacionados rastreados para rearranjos gênicos em BRCA1 e BRCA2 pela técnica de MLPA (multiplex ligation-dependent probe amplification) foram identificados 4 portadores de mutação germinativa, sendo a mutação em dois deles um rearranjo gênico no gene BRCA1 (1,4%) envolvendo sequencias Alu. Rearranjos gênicos em BRCA1 e BRCA2 são responsáveis por uma parcela das mutações em famílias HBOC Brasileiras. O presente estudo, envolvendo uma série grande de famílias com o fenótipo da síndrome HBOC, não identificou novos rearranjos fundadores, no entanto, demonstrou a presença de rearranjos tanto em BRCA1 quanto em BRCA2, reiterando a importância da busca ativa por estas alterações, que dificilmente são identificadas por técnicas convencionais de sequenciamento gênico. A técnica de MLPA associada a um protocolo específico para detecção da mutação fundadora Portuguesa c.156_157insAlu podem ser utilizadas como estratégia inicial de rastreamento de mutações em famílias Brasileiras com a síndrome. Os resultados apresentados aqui, no entanto, indicam que mutações serão identificadas em menos de 10% dos casos utilizando esta estratégia.Breast cancer is one of the most common malignancies affecting women worldwide. In Brazil, the State of Rio Grande do Sul has incidence rates and mortality from breast cancer are among the largest in the country. Approximately 5-10% of the cases are caused by germline mutations in predisposing genes including BRCA1 and BRCA2 are associated with the syndrome of breast and ovarian cancer Hereditary (Hereditary Breast and Ovarian Cancer Syndrome or HBOC, OMIM # 114480). The identification of inherited cases of breast cancer is important because affected individuals have cumulative risk life much higher than the population for developing cancer because of an affected family may also be at risk because there are measures of intensive screening and preventive interventions that can significantly decrease the risk of cancer in mutation carriers. The molecular diagnosis of HBOC syndrome is laborious and expensive due to the molecular heterogeneity of the disease. Families that have characteristics indicative of a cancer predisposition syndrome of hereditary breast and ovarian cancers, but are negative for mutations in BRCA1/2 have been tested for large rearrangements because these abnormalities have been identified as accounting for at least 10 % of all cases HBOC identifiable mutation, including large deletions or duplications. A recent study from Portugal, the founder showed that a rearrangement in exon 3 of BRCA2 occurs in 8% of HBOC families of the north. The objectives of this work included the verification of the frequency and characterization of gene rearrangements in BRCA1 and BRCA2 genes, including c.156_157insAlu founder mutation in exon 3 of BRCA2 mutations in Brazilian families at high risk for HBOC syndrome. In a group of 145 individuals at risk unrelated traced to c.156_157insAlu founder mutation in exon 3 of 3 found BRCA2 mutation carriers (prevalence 2%). In a group of 145 individuals at risk unrelated screened for gene rearrangements in BRCA1 and BRCA2 by the technique of MLPA (multiplex ligationdependent probe amplification) identified four carriers of germline mutation, and two of the mutation in a gene rearrangement in the gene BRCA1 (1.4%) involving Alu sequences. Gene rearrangements in BRCA1 and BRCA2 account for a portion of HBOC mutations in Brazilian families. This study, involving a large series of families with HBOC syndrome phenotype, no new rearrangements identified founders, however, showed the presence of rearrangements in both BRCA1 and BRCA2, reiterating the importance of active search for these changes, which hardly are identified by conventional techniques of gene sequencing. The technique of MLPA protocol associated with a specific mutation detection founder Portuguese c.156_157insAlu strategy can be used as initial screening for mutations in families with Brazilian syndrome. The results presented here, however, indicate mutations that will be identified in less than 10% of the cases using this strategy.
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Ramirez, Christina J. "BRCA genes : conserved regions and the potential effect of missense changes /". Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/5052.
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Turk, Casey M. "Paralemmin splice variants and mRNA and protein expression in breast cancers". Connect to this title, 2008. http://scholarworks.umass.edu/theses/194/.
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Warren, Curtis R. "Linker region of the BRCA2 protein increases chemoresistance to cisplatin: Screen for the characterization of cancer-associated variants". Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 84 p, 2009. http://proquest.umi.com/pqdweb?did=1885607671&sid=3&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Solyom, S. (Szilvia). "BRCA/Fanconi anemia pathway genes in hereditary predisposition to breast cancer". Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514294099.
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Abstract Two major genes are involved in hereditary predisposition to breast and ovarian cancer – BRCA1 and BRCA2. However, germline mutations in these tumor suppressors account for a maximum 20% of the familial breast cancer cases. A significant portion of the genes predisposing to this disease is unknown and therefore needs to be discovered. The aim of this study was to identify novel breast cancer susceptibility genes from the interweaving BRCA/Fanconi anemia (FA) pathway. Five candidate genes – MERIT40, ABRAXAS, BRIP1, CHK1, and FANCA – were screened for mutations by utilizing conformation-sensitive gel electrophoresis and sequencing, or with multiplex ligation-dependent probe amplification in blood DNA samples of Finnish familial breast cancer patients. Investigation of the MERIT40 gene revealed novel nucleotide changes, being the first report on mutation screening of this gene. None of the observed alterations, however, appeared to be disease related, suggesting that germline mutations in MERIT40 are rare or absent in breast cancer patients. A missense alteration (c.1082G>A, leading to Arg361Gln) was identified in ABRAXAS in 3 out of 125 Northern Finnish breast cancer families (2.4%), but not in any of the 867 healthy controls. The prevalence of the mutation between familial and control cases was statistically significantly different (p=0.002). ABRAXAS c.1082G>A appears to have pathological significance based on its exclusive occurrence in cancer cases, evolutionary conservation, disruption of a putative nuclear localization signal, reduced nuclear localization of the protein, and defective accumulation at DNA damage sites. The BRIP1 (FANCJ) and CHK1 genes were screened for large genomic rearrangements, but no abnormalities were detected, ruling out a significant contribution to breast cancer susceptibility in the Northern Finnish population. A novel large heterozygous deletion was identified in the FANCA gene in one out of 100 breast cancer families, removing the promoter and the first 12 exons. The deletion allele was not present in the tested controls, suggesting that it might contribute to breast cancer susceptibility. This is the first report on the association of a large-size germline deletion in a gene acting in the upstream part of the FA signaling pathway with familial breast cancerTiivistelmä BRCA1 ja BRCA2 ovat kaksi tärkeintä perinnöllisen rinta- ja munasarjasyövän alttiusgeeniä. Niissä esiintyvät ituradan muutokset selittävät kuitenkin vain noin 20 % familiaalisista rintasyöpätapauksista. Suurin osa alttiusgeeneistä on edelleen tunnistamatta ja näitä tekijöitä etsitään aktiivisesti. Tämän tutkimuksen tarkoituksena on ollut tunnistaa uusia alttiustekijöitä toisiinsa läheisesti liittyviltä BRCA/Fanconin anemia (FA) signaalinsiirtoreiteiltä. Viisi kandidaattigeeniä - MERIT40, ABRAXAS, BRIP1, CHK1 ja FANCA – kartoitettiin mutaatioiden suhteen suomalaisissa rintasyöpäperheissä käyttämällä konformaatiosensitiivistä geelielektroforeesia ja sekvensointia, tai multiplex ligation-dependent probe amplification- menetelmää. MERIT40-geenissä havaittiin useita aikaisemmin raportoimattomia nukleotidimuutoksia, mutta yhdenkään niistä ei havaittu liittyvän rintasyöpäalttiuteen. MERIT40-geenimuutosten mahdollista yhteyttä rintasyöpäalttiuteen ei ole tutkittu aikaisemmin. ABRAXAS-geenissä havaittiin missense-mutaatio (c.1082G>A, joka johtaa Arg361Gln aminohappokorvautumiseen) kolmessa pohjoissuomalaisessa rintasyöpäperheessä (3/125, 2.4 %). Muutosta ei havaittu terveissä kontrolleissa (N=867), ja ero mutaation esiintyvyydessä familiaalisten rintasyöpätapausten ja terveiden kontrollien välillä oli tilastollisesti merkitsevä (p=0.002). ABRAXAS c.1082G>A-muutos on todennäköisesti patogeeninen, sillä kyseinen aminohappopaikka on evolutiivisesti konservoitunut ja sijaitsee todennäköisellä tumaanohjaussignaalialueella. Funktionaaliset kokeet osoittivat, että mutatoitunut proteiinituote lokalisoitui villityypin proteiinia heikommin tumaan ja sen ohjautuminen DNA-vaurioalueille oli puutteellista. BRIP1- (FANCJ) ja CHK1-geeneistä etsittiin laajoja genomisia uudelleenjärjestelyjä, mutta niitä ei havaittu. Näin ollen kyseisillä muutoksilla ei ole merkittävää roolia perinnöllisessä rintasyöpäalttiudessa suomalaisessa väestössä. FANCA-geenissä havaittiin laaja heterotsygoottinen deleetio yhdessä tutkitusta 100 rintasyöpäperheestä. Deleetio poistaa geenin promoottorialueen lisäksi sen 12 ensimmäistä eksonia. Deleetioalleelia ei havaittu terveissä kontrolleissa, joten se mahdollisesti liittyy perinnölliseen rintasyöpäalttiuteen. Tutkimus on ensimmäinen, jossa raportoidaan laaja genominen deleetio FA-signaalinsiirtoreitin ylävirran geenissä familiaalisessa rintasyövässä
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Mozersky, J. "'Ashkenazi mutations' and the BRCA genes : genetics, disease and Jewish identity". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/19035/.
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This thesis explores the increased risk of genetic breast cancer for Ashkenazi Jews who are at significantly increased risk of carrying three specific mutations in the high risk breast cancer genes, BRCA1 and BRCA2. The Ashkenazi Jewish population has the highest known risk of genetic breast cancer and are the most well researched in relation to genetic disease. They are believed to have a particularly supportive and unique relationship with genetics, despite also having a history of discrimination that includes claims of biological inferiority. The use of racial or ethnic groups in genetic research is highly contentious and the implications for those populations being studied are usually assumed to be negative. There is also significant discussion about the potential of new genetic knowledge to transform individual and collective identity and alter how individuals conceive of themselves and the groups to which they belong. This thesis contributes to both of these areas of debate by exploring the implications for individuals of knowing that they are at increased risk of genetic breast cancer because they are of Ashkenazi Jewish origin. It specifically addresses whether being at increased risk has an impact on how Ashkenazi Jewish women feel about their own Jewish identity, whether they have concerns about current genetic research related to them, and if they are particularly supportive as if often claimed. Evidence is provided principally from qualitative interview material with Ashkenazi women at increased risk of genetic breast cancer as well as non high risk individuals. The qualitative data is supplemented by a quantitative survey. Ethnic identity can be an important mediating factor for the ways in which genetic knowledge is interpreted and genetic medicine can become intertwined with culturally specific issues. Ashkenazi Jews conceive of themselves, their history and their future in ways that are compatible with new genetic knowledge. While it is important not to assume there are necessarily damaging or transformative consequences for those populations that are the subjects of genetic research, there were implications for Ashkenazi women and their disease was interwoven with their identity in complex ways.
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Skoulidis, Ferdinandos. "Models of pancreatic carcinogenesis associated with inactivation of the BRCA2 breast cancer susceptibility gene". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609916.
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PRESNEAU, NADEGE. "Recherche de mutations constitutionnelles dans les genes de predispositions hereditaires aux cancers du sein et/ou de l'ovaire : brca-1, brca-2. recherche de nouveaux genes suppresseurs de tumeur impliques dans l'oncogenese mammaire". Clermont-Ferrand 2, 1999. http://www.theses.fr/1999CLF21122.
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Le gene brca-1 (breast cancer n 1), implique principalement dans une predisposition hereditaire au cancer du sein pre menopausique, localise sur le chromosome 17 en 17q12-21, a ete clone en 1994 par l'equipe de mark skolnik. Un deuxieme gene de predisposition hereditaire au cancer du sein, brca-2, a ete localise en 13q12-13 et clone en 1995. Au total, 52% des familles seraient porteuses d'une mutation brca-1, 35% porteuses d'une mutation brca-2 et 13% des familles liees a d'autres genes. Notre travail de these s'est ainsi inscrit dans un contexte general d'etude des predispositions hereditaires aux cancers du sein et/ou de l'ovaire. Cette etude a comporte deux objectifs majeurs. Notre etude a permis d'evaluer la reelle proportion de familles francaises a haut risque de cancers du sein et/ou de l'ovaire porteuse d'une mutation constitutionnelle du gene brca-1. En effet, des mutations germinales dans le gene brca-1 ont ete detectees dans 24% des familles francaises a haut risque de cancers du sein et/ou de l'ovaire, confirmant les resultats deja publies par d'autres equipes francaises. Puisque seulement 17 de nos familles sur les 70 etaient porteuses d'une mutation germinale de brca-1, nous avons recherche pour, ces meme 70 familles, l'eventuelle presence de mutations constitutionnelles dans le gene brca-2. Les premiers resultats de ce travail ont montre que 3 familles etaient porteuses d'une mutation du gene brca-2. Ainsi il apparait maintenant evident qu'il existe plusieurs genes de predispositions hereditaires aux cancers du sein et/ou des ovaires en plus de brca-1 et brca-2. Ainsi, la deuxieme partie de notre travail a consiste a rechercher des nouveaux genes de type oncosuppresseurs pouvant etre implique dans la tumorogenese mammaire. Ces genes peuvent etre impliques de facon indirecte par une eventuelle interaction avec les genes brca mais peuvent etre egalement impliques plus directement en etant eux-memes des genes candidats pour les genes brca-x. Par la technique de ddrt-pcr, nous avons ainsi recherche l'expression differentielle entre le tissu normal mammaire et le tissu tumoral mammaire d'une patiente (mme lp) dont la predisposition hereditaire semblait etre liee ni a brca-1 ni a brca-2. Ainsi, nous avons pu identifier plusieurs sequences differentielles dont une seule pourrait etre interessante a exploiter en clonant son adnc complet via une sequence genomique clone dans un vecteur de type pac (z84477 ncbi) avec la quelle notre sequence presente 100% d'homologie sur la totalite de sa sequence (82 pb).
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Ferlatte, Christy. "Patient preferences for an appropriate time for cancer genetic counseling and BRCA testing for women diagnosed with breast cancer". Waltham, Mass. : Brandeis University, 2009. http://dcoll.brandeis.edu/handle/10192/23193.
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Oliveira, Sarah Franco Vieira de. "Caracterização da expressão de genes da via de reparo do DNA FA-BRCA e do gene MTAP em carcinomas mamários". reponame:Repositório Institucional da UFPR, 2013. http://hdl.handle.net/1884/33791.
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Resumo: No Brasil os carcinomas mamários são os mais comuns entre as mulheres. O câncer de mama é uma doença heterogênea, cuja classificação é baseada na morfologia celular e na presença de receptores específicos. Esta classificação é útil na predição do prognóstico e no direcionamento do tratamento, e permitiu o desenvolvimento de terapias adjuvantes atualmente em uso na clínica. Estudos revelaram a presença de cinco subtipos intrínsecos de câncer de mama, quanto ao padrão de expressão gênica e às alterações genéticas: luminal-A, luminal-B, normal-like, ERBB2+ e basallike (incluindo-se aqui os tumores triplo negativos -TNBC). Considerando estes padrões de expressão, novas estratégias terapêuticas têm sido sugeridas. A análise da expressão de genes envolvidos nas vias de reparo do DNA e de outros genes importantes ao metabolismo celular, apresenta relevância clínica e para o desenvolvimento de novas estratégias terapêuticas. O objetivo principal do trabalho foi analisar a expressão de genes da via de reparo do DNA FA-BRCA, e do gene MTAP, propondo novas possibilidades terapêuticas em câncer de mama de acordo com o comportamento destes genes em diferentes subtipos tumorais. Foram utilizadas 46 amostras não-parafinizadas de carcinomas primários da mama, dez amostras não-parafinizadas de tecido não-tumoral da mama contralateral, 85 amostras paranifizadas de tumores de mama TNBC, 66 amostras parafinizadas de tumores de mama do grupo Luminal-A e sete linhagens celulares de carcinomas mamários. O gene FANCD2 foi aproximadamente duas vezes mais expresso no grupo tumoral (36) em relação ao grupo não-tumoral (10), quando se analisou um grupo de carcinomas ductais invasores. As amostras não-parafinizadas foram também classificadas conforme os subtipos intrínsecos do câncer de mama. O gene BRCA1 foi aproximadamente três vezes menos expresso no grupo Luminal-B (14) em relação ao grupo Luminal-A (23). Nas amostras parafinizadas, o gene MTAP se mostrou aproximadamente duas vezes menos expresso no grupo TNBC (85) em relação ao grupo Luminal-A (66). MTAP foi inativado em uma linhagem celular que expressa o gene, e foram realizados ensaios citotóxicos com fármacos que interferem na via da biossíntese de poliaminas. As células MTAP-negativas apresentaram maior sensibilidade ao fármaco 5'- fluorouracil (5'-FU) em relação às células MTAP-positivas. O aumento da expressão gênica de FANCD2 no grupo tumoral pode ser um indicador da ativação da via, o que contribui para o processo carcinogênico, e também já foi correlacionado com a resistência à ciclofosfamida e outros quimioterápicos. A redução da expressão de BRCA1 no grupo Luminal-B é considerada um indicador para a escolha de terapias adjuvantes baseadas em cisplatina, e para que tratamentos baseados em taxóis sejam evitados, devido ao maior risco de resistência. Tumores com expressão reduzida de MTAP, como o grupo TNBC, são mais sensíveis a inibidores da síntese de poliaminas, como o 5'- FU. Nossos resultados corroboram um esquema terapêutico proposto recentemente para tumores MTAP-negativos, baseado no uso de análogos de poliaminas e do substato MTA, sugerindo novas possibilidades terapêuticas para pacientes TNBC. O padrão de expressão dos genes FANCD2, BRCA1 e MTAP apresenta forte relevância clínica, influenciando a resposta a diversos fármacos, e também atuando como novos alvos terapêuticos no câncer de mama.
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Paladini, L. "BIOLOGICAL SIGNIFICANCE OF ALTERATIONS IN BRCA1 AND BRCA2 GENES AND RESPONSE TO DNA DAMAGE AGENTS IN HEREDITARY BREAST CANCER". Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/488444.
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Background: Although the large number of studies investigating BRCA mutations and their clinical role in different populations and ethnicities, there is a lack of a systematic analysis on these alterations in Italian cohorts, including the analysis of Variants of Unknown biological and clinical Significance (VUS). Moreover, correct management of breast cancer patients tested positive for alterations in BRCA1 or BRCA2 genes is still controversial. We aimed to assess the biological and clinical relevance of BRCA alterations in a consecutive cohort of hereditary breast cancer patients, with particular attention to VUS.
Methods: Genetic and clinical data from 366 patients with familial history of breast cancer were reviewed. The association between clinical-pathological, molecular data, and breast cancer patient subgroups was assessed. BRCA1/2 and γ-H2AX expression levels were assessed by qRT-PCR and IHC for all tumors. In silico protein prediction models were computed for VUS with potential clinical significance. Cell proliferation and apoptosis assays for CRISPR/Ca9s-generated mutant MDA-MB-231 cell line were performed to evaluate the sensitivity of specific VUS to DNA damage agents.
Results: Overall, 73 breast cancer patients (20%) tested positive for BRCA1/2 alterations. BRCA1 and BRCA2 mutations were reported in 34 (46.5%) and 15 (20.5%) patients, respectively. Two patients (3%) showed two concurrent mutations in both genes. Twenty-two patients (30%) tested positive for VUS. Breast cancer family history and early onset of disease were significantly associated with BRCA1 (p < 0.001) and BRCA2 (p = 0.045 and p = 0.005) mutations. Triple-negative histotype, grading 3, and high Ki-67 levels were significantly associated with BRCA1 mutations (p < 0.001). Molecular, in silico and in vitro experiments confirmed the deleterious effect of BRCA1 c.5509T>C VUS, which was associated with significant high levels of DNA damage and greater sensitivity to Olaparib compared to Cisplatin treatment.
Conclusions: Our study supports the deleterious effect of the BRCA1 c.5509T>C VUS in hereditary breast cancer patients, and suggests that breast cancer patient carriers of this variant could benefit from an intense surveillance and from a single agent treatment with Olaparib avoiding various side effects of chemotherapy treatment.
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Chan, Yuen-kwong. "Study on the role of genetic and epigenetic factors in relation to the BRCA genes in epithelial ovarian cancers". Click to view the E-thesis via HKUTO, 2002. http://sunzi.lib.hku.hk/hkuto/record/B42576726.
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Batista, Rui Pedro Monteiro. "Caracterização das mutações dos genes BRCA1 e BRCA2". Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10136.
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Mestrado em Biologia Molecular e CelularO cancro da mama é o tipo de neoplasia maligna mais incidente nas mulheres a nível mundial. Na maior parte dos casos tem origem esporádica, mas estima-se que cerca de 7% tem origem hereditária, relacionada com a herança genética de alguma mutação patogénica em genes de suscetibilidade para este cancro. A causa mais frequente de cancro hereditário da mama/ovário é a alteração de um dos genes BRCA (BRCA1 ou BRCA2). De fato as mutações germinativas destes genes são responsáveis por cerca de 50% dos casos de cancro hereditário da mama e/ou ovário. São ainda poucos os dados referentes ao perfil de mutações destes genes na população portuguesa, para além da descrição de uma mutação fundadora no gene BRCA2. Pretendeu-se com o presente estudo caracterizar, numa amostra de doentes portugueses com suspeita de cancro hereditário da mama/ovário, as mutações destes dois genes, avaliando os diferentes tipos de mutações encontradas, a prevalência de mutações comprovadamente patogénicas e, nomeadamente da mutação fundadora portuguesa. Pretendeu-se também testar o algoritmo de cálculo BRCAPro® no auxílio ao recrutamento para estudo genético de pacientes com suspeita de HBOC. Dos 121 casos estudados por DGGE/sequenciação direta/MLPA, foram detetados 42 casos (34,7%) com alterações num dos BRCA’s (excluindo polimorfismos), correspondendo a 42-45 alelos mutados. No entanto, apenas 8,3% dos casos continham mutações comprovadamente patogénicas, representando a mutação fundadora portuguesa 40% das mesmas. Comparativamente a outros estudos na população portuguesa, a prevalência de mutações patogénicas no nosso estudo foi inferior, com uma sobrerepresentação da mutação fundadora, o que poderá ser explicado por diferentes critérios de referenciação e/ou composição das amostras estudadas. O algoritmo BRCAPro® revelou-se útil como instrumento de cálculo de probabilidade de mutação patogénica nos genes BRCA1 e BRCA2, embora não permita substituir o critério médico na de seleção de pacientes para estudo genético destes genes.
Breast cancer is the type most common malignant neoplasm in women worldwide. In most cases arises sporadically, but it is estimated that about 7% have a hereditary origin, related to the genetic inheritance of some pathogenic mutation in susceptibility genes for this cancer. The most frequent cause of hereditary breast/ovarian cancer is an alteration in one of the two BRCA genes, the BRCA1 and BRCA2. Germline mutations in these two genes are responsible for about 50% of cases with hereditary breast and ovarian cancer. Currently, few data is available referring to the mutation profile in the Portuguese population, besides the identification of a founder mutation in the BRCA2 gene. It was intended with this study to characterize, in a sample constituted of patients with suspicion of hereditary breast/cancer, mutations of these two genes, evaluating the different types of mutations found, the prevalence of pathogenic mutations, particularly the Portuguese founder mutation. It was also intended to test the algorithm BRCAPro®, in the aid of recruitment of patients for genetic testing with suspected HBOC. Of the 121 cases studied by DGGE/direct sequencing/MLPA, we detected 42 cases (34,7%) containing alterations in one of the BRCA genes (excluding polymorphisms), corresponding to 42-45 mutated alleles. After analysis, only 8.3% of the cases had deleterious mutations, with the founder Portuguese mutation representing 40% of those. Comparing to other studies in the Portuguese population, the prevalence of pathogenic mutations found in this study was smaller, with an overexpression of the Portuguese founder mutation. That can be explained by the use of different clinical criteria in the recruitment of patients for genetic study and/or differences in the composition of the cohort of cases. The BRCAPro® algorithm as proved useful as a tool for the calculation of mutation probability in the BRCA1 and BRCA2 genes, although it doesn’t allow to substitute the medical criteria in the selection of patients for genetic study in this two genes.
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Escobar, Karina Augusto. "Determinação de mutações e polimorfismo nos genes BRCA1 e BRCA2 em pacientes com câncer de mama com indicação para teste genético". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-05092011-152557/.
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Introdução: Mutações nos genes BRCA1 e BRCA2 são responsáveis por cerca de 50% dos casos de câncer de mama e/ou ovário hereditários. Atualmente não conhecemos o perfil de mutações destes genes na população brasileira, com exceção de mutações fundadoras que ocorrem em grupos étnicos específicos. Objetivos: Detectar mutações e polimorfismos nos genes BRCA1 e BRCA2 em 73 pacientes com câncer de mama selecionadas para o teste genético. Casuística e métodos: Realizamos o sequenciamento direto e o teste de MLPA para os genes BRCA1 e BRCA2 em 73 indivíduos, sendo 63 pacientes com câncer de mama com risco maior ou igual a 10% de acordo com os critérios de Frank, Evans e BRCAPRO, dois pacientes com câncer de ovário e oito indivíduos saudáveis com forte histórico familiar de câncer ligado a mutações em BRCA1 e/ou BRCA2. Resultados: Encontramos 60 mutações no gene BRCA1: 13 alterações missense (incluindo a deletéria R71G), sete mutações sinônimas, uma mutação frameshift (a deletéria 5382insC), uma mutação nonsense (a deletéria R1751X), uma deleção in frame, uma alteração 3UTR e 36 variantes intrônicas. Em BRCA2 encontramos 57 mutações, entre as quais 26 mutações missense, uma alteração 5UTR, 11 mutações sinônimas, 14 variantes intrônicas, duas mutações nonsense (as deletérias R2318X e R3128X) e três mutações frameshift deletérias (5844del5, 6633del5 e 6610insTT). Nenhuma mutação foi detectada pelo teste de MLPA. Discussão e considerações finais: Nove de 73 indivíduos estudados são portadores de mutações deletérias, sendo que a mutação fundadora Ashkenazi 5382insC foi encontrada em duas pacientes não aparentadas e que outro grupo de pesquisa já reportou sua alta frequência numa população paulistana. As alterações de significado clínico desconhecido foram encontradas em toda a extensão dos genes BRCA1 e BRCA2 e são inúmeras. Algumas apareceram em somente uma paciente, o que nos leva a pensar que talvez uma ou algumas destas mutações tenham algum efeito patogênico, como a mutação 6610insTT, que gera uma proteína incompleta e foi encontrada em três gerações de uma família. A técnica de MLPA não detectou grandes rearranjos em ambos os genes, mostrando que este tipo de alteração genética não é freqüente em nossa coorte e que talvez esta seja uma característica mais prevalente em populações menos miscigenadas. Salientamos, portanto, a importância de ampliar este estudo e de estimular pesquisas futuras, visando um aconselhamento genético eficiente, com a diminuição do número de casos inconclusivos gerados pelas variantes de significado indeterminado e o acompanhamento clínico das famíliasIntroduction: Mutation in BRCA1 and BRCA2 genes are responsible for more than 50% of hereditarian breast and ovarian cancer cases. Nowadays, we still dont know the Brazilian mutation profile for these genes, except when founder mutations occur in specific ethnic groups. Objetives: Detection of mutation and polymorphisms in BRCA1 and BRCA2 genes in 73 breast cancer patients selected for genetic testing. Casuistic and methods: we have realized direct sequencing of BRCA1 and BRCA2 in 73 patients, whose 63 have had breast cancer and showed at least 10% of risk according to Frank, Evans and BRCAPRO, two patients with ovarian cancer and eight healthy individuals of strong family history of cancer linked to mutations in BRCA1 and BRCA2. Results: We have found 60 mutations in BRCA1: 13 missense mutations (including the deleterious R71G), seven synonymous mutations, one frameshift mutation (the deleterious 5382insC), one nonsense mutation (the deleterious R1751X), one in-frame deletion, one 3UTR mutation and 36 intronic variants. In BRCA2 we have found 57 mutations: 26 missense mutations, one 5UTR mutation, 11 synonymous mutations, 14 intronic variants, two nonsense mutations (the deleterious R2318X and R3128X) and three frameshift mutations (5844del5, 6610insTT and 6633del5). No mutation was detected by MLPA technique. Discussion and final considerations: Nine of 73 studied individuals carry deleterious mutations. Among them, the Ashkenazi founder mutation 5382insC has been found in two unrelated patients and it was previously reported by another research group for its high prevalence on a population from São Paulo. Alterations of unknown clinical significance have been found all over BRCA1 and BRCA2 gene extension and are countless. Some of them are shown only in one patient, leading us to think that maybe one or a few might have a pathogenic effect, like 6610insTT, which leads to a BRCA2 incomplete protein and was shown in 3 generations of a family. MLPA technique have not detected large genomic rearrangements in both genes, showing that this kind of mutation is not frequent on our cohort and maybe this genetic alteration characterizes less miscigenated populations. So, we emphasize the importance of enlarge this study and stimulate future researches, aiming an efficient genetic counseling, decreasing inconclusive cases generated by unknown clinical significance variants, and follow up of affected families
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Elliott, Diana. "The impact of genetic counselling for familial breast cancer on women's psychological distress, risk perception and understanding of BRCA testing". University of Western Australia. School of Population Health, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0190.
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[Truncated abstract] Background: A review of the literature indicated there was a need for more long-term randomised controlled studies on the effects of BRCA counselling/testing on high risk women, including improved strategies for risk communication. Reviews have also shown women are confused about the significance of inconclusive or non informative results with a need for more research in this area. Aims: The general aim of this study was to evaluate the impact of breast cancer genetic counselling on psychological distress levels, perception of risk, genetic knowledge and understanding of BRCA testing/test results in a cohort of 207 women from high risk breast cancer families who were referred for genetic counselling in Perth during the period 1997 to 2001. Short- and long-term impact of BRCA genetic counselling/testing was determined in women with and without cancer in a randomised controlled trial as part of which women were randomised to either receive immediate versus delayed genetic counselling. This included family communication patterns before BRCA testing, anticipated outcomes of testing on oneself and family including intentions for result disclosure. Comprehension of index and predictive BRCA testing with possible results was assessed both in the short- and the long-term and understanding of individual or family BRCA test results was evaluated at long-term. The effect of genetic counselling on breast cancer risk perception in unaffected women was evaluated. This study considered a theoretical framework of educational learning theories to provide a basis for risk communication with possible relevance for future research. ... Only 25% of the original study population (52/207) reported BRCA results and women's understanding of results is concerning. Key findings were: 1. The majority of affected women received an inconclusive result. 2. Out of twelve unaffected women who reported results, seven were inconclusive which are not congruent with predictive testing. This implies that these women did not understand their test result. 3. A minority of untested relatives did not know whether a family mutation had or had not been found in their tested family member or what their actual test result was. This implies either a lack of disclosure or that woman did not understand the rationale for and significance of testing for a family mutation. 4. Three relatives did not understand a positive result was a mutation. Conclusion: The implication of this research for breast cancer counselling and testing services is that women who wait for counselling are no worse off in terms of short- or long-term general psychological distress than women who receive the intervention early. There is a suggestion that unaffected women without the disease found counselling more advantageous than affected women. The meaning of BRCA results as reported by women is concerning particularly women's understanding of negative and inconclusive results and further research is needed in this area. Too much information presented at counselling may affect women's comprehension of risk, BRCA testing and future test results and further research is required to evaluate the effects of information overload.
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Santana, dos santos Elizabeth. "Contribution of the Missense and Non-Coding BRCA1/2 Variants for the Hereditary Predisposition and Response to Treatment of Breast and Ovarian Cancers Assessment of the Functional Impact of Germline BRCA1/2 Variants Located in Non- Coding Regions in Families with Breast and/or Ovarian Cancer Predisposition Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS027.
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Les cancers de l'ovaire et du sein sont définis par les principales voies impliquées dans la tumorigénèse. Dans les cancers héréditaires du sein/ovaire (HBOC), les tumeurs présentant des variants pathogènes (PV) de BRCA1/2 présentent une altération de la réparation de l'ADN par recombinaison homologue (RH). Des années après la découverte des gènes BRCA1/2, les PV ont été uniquement recherchés sur l'ADN constitutionnel. Aujourd’hui, cette information est également recherchée au niveau tumoral car en plus de leur utilité pour améliorer le conseil génétique, elle est aussi impliquée dans le choix thérapeutique. Cependant, les données recueillies indiquent que les PV inactivant la protéine ne seraient pas l’unique mécanisme d’inactivation de la voie de réparation de l’ADN par RH. Dans ce contexte, l'objectif principal de cette thèse est d'identifier des mécanismes alternatifs d'inactivation de la voie HR pour améliorer à la fois: le conseil génétique et la prise en charge thérapeutique. À cette fin, nous avons tenté de contribuer à la classification de variants non-codants et faux-sens (autre que provoquant un stop prématuré) de BRCA1/2 et également recherché de nouveaux biomarqueurs de réponse thérapeutique dans d’autres gènes de la voie de HR.Nous avons décrit des variants constitutionnels dans des régions potentiellement importantes de régulation des gènes BRCA1 et BRCA2, et démontré qu'une partie d'entre eux étaient fonctionnellement actifs à mettre en lien avec la pathogénicité. Nous avons également exploré les caractéristiques moléculaires des tumeurs du sein et de l'ovaire des porteurs des variants BRCA1 et observé une prédominance de la perte de l'allèle sauvage pour les tumeurs des porteurs de variants pathogènes. Etant donné ces résultats, nous proposons d’intégrer les informations de LOH dans le modèle multifactoriel de classification des variants BRCA1. Enfin, nous avons mis en évidence des mécanismes alternatifs d'inactivation de la voie RH, dans une cohorte de patientes avec un cancer de l'ovaire présentant une excellente réponse aux platines, y compris des mutations constitutionnelles et somatiques des gènes BRCA1/2, l'hyperméthylation du promoteur BRCA1 ainsi que des mutations dans d'autres gènes de la voie RHOvarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. In hereditary breast/ovarian cancers (HBOC), tumors with BRCA1/2 pathogenic variants (PV) present an impairment of DNA repair by homologous recombination (HR). For many years, BRCA1/2 PV were only searched on germline DNA. Currently, this information is also searched at tumor level to personalize treatment. Even so, the reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of HR deficient signature.Gathered evidence indicates that protein inactivating PV may not be the only mechanism of HR dysfunction. In this context, the main objective of this thesis is to identify alternative mechanisms of HR inactivation to improve both: genetic counseling and therapeutic response. For this purpose, we have attempted to contribute to non-coding and missense (other than premature stop codon) BRCA1/2 variant classification and searched for new biomarkers of therapeutic response to DNA damage agents in other HR genes.We identified germline variants in key transcriptional regulatory elements of BRCA1 and BRCA2, and demonstrated that part of them were functionally active and had additional arguments suggesting pathogenicity. We also explored molecular features of breast and ovarian tumors from BRCA1 variant carriers and observed a predominance of loss of the wild-type allele. Conforming to this evidence, we propose to incorporate LOH information, into the multifactorial model for BRCA1 variant classification. Finally, besides the enrichment of BRCA1/2 germline and somatic PV, we described alternative mechanisms of HR inactivation in a OC population presenting optimal response to platinum-based chemotherapy, including BRCA1 promoter hypermethylation and also mutations in other genes of HR pathway
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Rapakko, K. (Katrin). "Hereditary predisposition to breast cancer—evaluation of candidate genes". Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284502.
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Abstract
In Western countries, breast and ovarian cancer are among the most frequent malignancies affecting women. Approximately 5–10% of the cases in the general population have been suggested to be attributed to inherited disease susceptibility. BRCA1 and BRCA2 are the main genes associated with predisposition to breast and ovarian cancer. Mutations in these two genes explain a major part of the families displaying a large number of early-onset breast and/or ovarian cancers, but at least one third of the cases appear to be influenced by other, as yet unidentified genes. Therefore, it is likely that defects in other cancer predisposing genes, perhaps associated with lower disease penetrance and action in a polygenic context, will also be discovered.
In the present study, the contribution of germline mutations in putative breast and/or ovarian cancer susceptibility genes, based on their biological function, has been investigated in Finnish breast cancer families. The role of large genomic deletions or other rearrangements in the BRCA1 and BRCA2 genes was evaluated by Southern blot analysis, and mutation analysis of TP53, RAD51, the BRC repeats of BRCA2, and 53BP1 was performed by conformation sensitive gel electrophoresis and DNA sequencing.
Germline TP53 mutations were searched for in 108 Finnish breast cancer families without BRCA1 or BRCA2 alterations. In this study, the pathogenic TP53 germline mutation, Arg248Gln, was identified in only one family. This family showed a strong family history of breast cancer and other cancers also fulfilling the criteria for Li-Fraumeni-like syndrome. Germline TP53 mutations are expected to be found in cancer families with clinical features seen in Li-Fraumeni or Li-Fraumeni-like syndromes.
In this study, large deletions in BRCA1 and BRCA2 were not observed in 82 breast and/or ovarian cancer families. Likewise, no disease-related aberrations were detected in RAD51, the BRC repeats of BRCA2 or 53BP1 in the 126 breast and/or ovarian cancer families studied. The obtained results were validated by comparing to the occurrence in 288–300 female cancer-free control individuals. These results do not support the hypothesis that alterations in these particular genomic regions play a significant role in breast cancer predisposition in Finland. Thus, there are still genes to be discovered to explain the molecular background of breast cancer.
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Huusko, P. (Pia). "Predisposing genes in hereditary breast and ovarian cancer". Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254422.
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Abstract
In the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland. In the 15 Turkish cancer families studied, 5382insC and 5622C→T were detected in BRCA1, and 3414delTCAG in BRCA2. The novel 3414del4 mutation was found in a family with a case of male breast cancer.
In order to determine their ages and origin, 9 recurrent Finnish BRCA1 and BRCA2 mutations were studied further as regards haplotype conservation. Common origins approximately 18–80 generations (400–1600 years) ago were demonstrated for all studied mutations by partial haplotype sharing. The majority of the mutations showed geographical clustering, supporting the theory of regional founder effects. Four of the nine mutations are unique for Finland, whereas five have also been seen elsewhere. Mutations in the 5' end of BRCA1 tend to predispose individuals to ovarian cancer and those found in the 3' end to breast cancer. The age of ovarian cancer onset was significantly lower for BRCA1 (51 years) than for BRCA2 mutation carriers (61 years).
Germline TP53 mutations were sought in the Finnish breast cancer families found to be negative after BRCA1 and BRCA2 screening but who exhibited some phenotypic features of the Li-Fraumeni syndrome. The Asn235Ser was found in a family displaying Li-Fraumeni syndrome phenotype and the Tyr220Cys in a family with a milder Li-Fraumeni-like phenotype. The nature of both mutations as cancer-predisposing alterations was supported by means of loss of heterozygosity (LOH) and p53 immunohistochemistry studies.
Regional clustering of BRCA1 and BRCA2 founder mutations enables targeted genetic tests including especially those mutations characteristic of the birthplace of each patient. Additional genes are likely to explain a large proportion of the inherited susceptibility to breast cancer in particular. Germline TP53 mutations are expected to be found in the breast cancer families with other clinical features seen in the Li-Fraumeni syndrome.
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RAMALHO, Eduardo Augusto Vasconcelos de Freitas. "Avaliação de alterações nos genes p53, BRCA1 em Carcinoma Ductal Invasivo de Mama (CDI)". Universidade Federal de Pernambuco, 2012. https://repositorio.ufpe.br/handle/123456789/10853.
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Sabe-se que os genes p53, BRCA1 e BRCA2 apresentam a característica em comum de serem considerados supressores tumorais. Eventos genéticos e epigenéticos são frequentes ao longo de todo o genoma humano. Mutações somáticas são passíveis de ocorrer nas regiões codificantes de genes específicos, alterando sua sequência e gerando proteínas mutantes, as quais resultam numa alteração de sua capacidade funcional ou até mesmo a perda dela. Este trabalho objetivou avaliar alterações epigenéticas nas regiões promotoras dos genes BRCA1 e BRCA2 através da técnica de PCR para Metilação Específica (MSP) e correlacionar mutações pontuais nos exons 4 e 7 do gene p53 como fator de risco para o carcinoma ductal invasivo (CDI) de mama na população feminina do Recife atendida no Hospital das Clínicas (HCUFPE). Cinquenta biópsias de mama diagnosticadas com CDI fixadas em formalina e embebidas em parafina foram obtidas do Setor de Anatomia Patológica do HC-PE e cinco amostras de tecido mamário de mulheres submetidas à mastectomia estética foram usadas como controle normal. O DNA das amostras foram extraídos e, então, amplificados por MSP. Para avaliação do perfil mutacional utilizou-se a técnica de PCR-RFLP (Restriction Fragment Length Polymorphism) com as enzimas BstUI e HaeIII para verificação dos polimorfismos nos exons 4 e 7, respectivamente. A frequência no padrão de metilação para o gene BRCA2 foi de 46,9% enquanto a frequência de mutações pontuais nos códons 72 (exon 4) e 249 (exon 7) do gene p53 foram de 91,8% e 8,1%, respectivamente. Para o BRCA1 os resultados obtidos foram inconsistentes quanto ao seu padrão de metilação. Os resultados mostraram que o polimorfismo do códon 72 apresentou-se estatisticamente significante para metástase podendo ser utilizado como um potencial biomarcador auxiliar no diagnóstico de carcinoma ductal invasivo de mama humana.
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Margolin, Sara. "Family history and breast cancer susceptibility : clinical and molecular studies /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-868-1/.
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Maguire, Paula. "Investigation of the genetic basis of familial non-BRCA1/2 breast cancer /". Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-602-6/.
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Alwahiby, Suliman Abdullah M. "Molecular cytogenetic analysis of telomeres in cells with mutant BRCA1 and BRCA2 genes". Thesis, Brunel University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425381.
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Liu, Wei. "Genetic analysis of the BRCA1 and BRCA2 genes in breast cancer of Hong Kong Chinese". Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39558848.
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Vallée, Maxime. "Design of an internet tool to assess variants of uncertain clinical significance in high-risk breast cancer genes BRCA1 and BRCA2". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10193.
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Des mutations germinales dans les gènes majeurs du cancer du sein BRCA1 et BRCA2 sont responsables de la maladie chez les patientes cumulant histoire familiale et apparition du cancer à un jeune âge. Environ 15% des femmes testées pour les mutations de BRCA1 et BRCA2 sont porteuses d’une mutation clairement pathogénique dans un des deux gènes. Cependant, des variants de signification clinique incertaine (VUS pour "variants of uncertain clinical significance") sont détectés dans 5% à 15% des cas testés. Pour évaluer la signification clinique des VUS, le Breast cancer Infomation Core (BIC) a développé un modèle Bayésien intégré, basé sur des données d'observations. Align-GVGD, un algorithme d'évaluation des substitutions faux-sens basé sur l'histoire évolutionnaire de la protéine fournit la probabilité a priori du modèle. Cependant, lorsqu'une substitution silencieuse est détectée, elle sera jugée comme neutre par l'évaluation in silico. Pourtant, une mutation au niveau de l'ARNm peut perturber la mécanique de l'épissage, par deux moyens principaux: endommagement des sites sauvages d'épissage, ou la création de sites exoniques d'épissage de novo. Notre premier objectif est de rassembler les variants déjà publiés, de les re-analyser avec le modèle d'évaluation intégrée. Nous voulons extraire le plus de variants publiés premièrement sous le statut de VUS vers un statut plus informatif, avec des recommandations cliniques associées. Par la suite, nous voulons étendre le modèle pour évaluer plus de variants, plus précisément, en intégrant l'évaluation des perturbations de l'épissage. Finalement, nous serons capable de présenter et de fournir ces informations librement sur Internet, via une interface web populaire, une Leiden Open Variation Database (LOVD)Germline mutations in major breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for the disease for high-risk patients (patients with early onset and familial history of breast cancer). Around 15% of screened women for BRCA1 and BRCA2 mutations carry one clearly pathogenic mutation in one of those two genes. However, variants of uncertain clinical significance (VUS) are detected in 5% to 15% of tested patients. To assess clinical significance of VUS, the Breast cancer Information Core (BIC) has developed a Bayesian integrated model, based on observational data. Align-GVGD, an algorithm evaluating damage of missense substitutions based on the evolutionary history of the protein, is providing the prior probability of the model. However, whenever a silent substitution arise, it is firstly treated as neutral by the in silico assessment. Indeed, a mutation at the mRNA level can disrupt the splicing machinery by two main means: damaging wild-type splice sites, or creating exonic de novo splice sites. Our first goal is to be a central repository of already published variants, to re-analyze them using the unified integrated evaluation model. We would like to extract the most variants from the original published status of VUS to a more informative status, with associated clinical recommendations. Then we would like to extend the model to be able to evaluate more variants more precisely by adding the splicing damages assessment in the integrated evaluation. In the end, we will be able to provide these informations freely on Internet, via a widely use web interface, a Leiden Open Variation Database (LOVD)
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Goveia, Rebeca Mota. "Análise de deleção/ duplicação nos genes BRCA1 e BRCA2 em pacientes de Goiás-Brasil com suspeita da síndrome do câncer de mama e ovário hereditário". Universidade Federal de Goiás, 2018. http://repositorio.bc.ufg.br/tede/handle/tede/8723.
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Introduction: Breast cancer is the second most common cancer in the world, and the most common among women, only 5% to 10% are hereditary and half of them are caused by hereditary breast and ovarian cancer (HBOC) , caused by variations in the BRCA1 and BRCA2 genes. Objectives: The present study aimed to identify the prevalence of deletions and duplications in BRCA1 and BRCA2 genes in breast cancer patients in Goiás, Brazil. Materials and methods: We evaluated 46 breast cancer patients who met National Comprehensive Cancer Network (NCCN) criteria for HBOC syndrome screening. A 4 ml blood sample was collected for DNA extraction using commercial kit and the MLPA (Multiplex Ligation Dependent Probe Amplification) technique was performed using the SALSA MLPA P002 BRCA1 and SALSA MLPA P045 BRCA2 / CHECK2 kits. Results and discussion: The majority of the patients were female (97.83%) and the mean age of the patients was 37.52 years. In this group, 43.47% of the patients were younger than 35 years at the time of diagnosis and 35% of them were diagnosed with triple negative tumors. The most common molecular subtype was luminal A (46.2%) followed by triple negative tumors (28.20%). No patient was found with rearrangements in BRCA1. In the BRCA2 gene, one patient (2.12%) presented a false positive result for the heterozygous deletion of exon 27, which may have been caused by the presence of a small change in the probe binding region. Conclusion: This was the first study performed to analyze large deletions and duplications in patients from the central-western region of Brazil. We can conclude that the frequency of large deletions and duplications in the BRCA1 and BRCA2 genes in the Goian population is low.
Introdução: O câncer de mama é o segundo tipo de câncer mais freqüente no mundo, e o mais comum entre as mulheres, apenas 5% a 10% são hereditários e metade deles são causados pela síndrome do câncer de mama e ovário hereditário (HBOC), causada por variações nos genes BRCA1 e BRCA2. Objetivos: O presente estudo teve como objetivo identificar a prevalência de deleções e duplicações nos genes BRCA1 e BRCA2 em pacientes com câncer de mama no estado de Goiás, Brasil. Materiais e métodos: Avaliamos 46 pacientes com câncer de mama que atenderam aos critérios do National Comprehensive Cancer Network (NCCN) para pesquisa da síndrome HBOC. Foi coletada uma amostra de sangue de 4 ml para extração de DNA usando kit comercial e a técnica MLPA (Multiplex Ligation Dependent Probe Amplification) foi realizada usando os kits SALSA MLPA P002 BRCA1 e SALSA MLPA P045 BRCA2 / CHECK2. Resultados e discussão: A maioria dos pacientes era do sexo feminino (97.83%) e a idade média dos pacientes era de 37,52 anos. Neste grupo 43.47% dos pacientes possuíam idade inferior a 35 anos no momento do diagnóstico sendo que 35% destes foram diagnosticados com tumores triplo negativo. O subtipo molecular mais comum foi o luminal A (46.2%) seguido de tumores triplo negativos (28.20%). Nenhum paciente foi encontrado com rearranjos no gene BRCA1. No gene BRCA2, um paciente (2,12%) apresentou um resultado falso positivo para a deleção em heterozigoze do éxon 27, fato que pode ter sido ocasionado pela presença de uma pequena alteração na região de ligação da sonda. Conclusão: Este foi o primeiro estudo realizado para análise de grandes deleções e duplicações em pacientes da região centro-oeste do Brasil. Podemos concluir que a frequência de grandes deleções e duplicações nos genes BRCA1 e BRCA2 na população goiana é baixa.
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Liu, Wei, i 劉蔚. "Genetic analysis of the BRCA1 and BRCA2 genes in breast cancer of HongKong Chinese". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39558848.
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Diz, Maria Del Pilar Estevez. "Impacto do encaminhamento para ambulatório de câncer hereditário na qualidade de vida de pacientes portadores de câncer de mama". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-20082007-161259/.
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Neste trabalho, medimos o impacto da avaliação do risco de mutações dos genes BRCA1/2 na qualidade de vida de pacientes com câncer de mama, avaliada pelos questionários EORTC QLQ-C30 e QLQ-BR23. Convidamos 282 pacientes a participar, respondendo aos questionários antes e depois da avaliação do risco pelos métodos de Frank, Evans e BRCAPRO. Consideramos risco elevado pelo menos 10%. 272 foram incluídas e 198 completaram o estudo. Nas 180 avaliáveis, a idade mediana das pacientes foi de 53 anos com desvio padrão de 11,5 anos e, em 89, o tempo desde o diagnóstico de menos de 36 meses. 40 pacientes estavam em seguimento e 137 em hormonioterapia. Não detectamos alterações significativas da qualidade de vida com a determinação do risco para mutações. Houve diferença significativa entre imagem corporal negativa e cirurgia conservadora da mama (p<0,001). Classificamos 45 como risco elevado pelo método de Frank, 35 pelo BRCAPRO e 21 por Evans, sendo que em 12 dessas pacientes houve concordância dos três métodos juntos. Concluímos que, apesar do grande interesse demonstrado pelas pacientes em participar no estudo, a determinação do risco não interferiu na qualidade de vida dessas pacientes. Aparentemente, as informações sobre hereditariedade são desejadas, mas não acarretam estresse adicional e deveriam ser prestadas, pois o número de pacientes com risco elevado é semelhante ao indicado em outras populações. Além disso, a baixa concordância entre os métodos utilizados indica a necessidade de definir parâmetros para determinação de risco em nosso meio.Here we evaluated the impact of breast cancer hereditary cancer risk evaluation on the quality of life in a population of breast cancer patients, as measured by the EORTC questionnaires QLQ-C30 and QLQ-BR23. Of the 282 invited patients, 272 agree to participate and answered QLQ before and after the risk determination by Frank, Evans and BRCAPRO methods. High risk was defined as at least 10%. Overall 198 pts completed the study. In the 180 evaluable patients, median age was 53 (+11,5) years old and time since diagnosis was less than 36 months in 89. We did not detected significant differences in quality of life parameters after risk determination, except for negative body image and mastectomy/conservative surgery (p<0.001) There were 45 patients classified as high risk by Frank, 35 by the BRCAPRO and 21 by Evans, agreement being reached in 12. We conclude that pts wish to know about their hereditary breast cancer risk, and this do not cause necessarily more stress. Apart from that, there is a need for local methods of risk calculation.
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Becker, Alexandra Angela [Verfasser]. "Funktionelle Analyse unklassifizierter Varianten der Gene BRCA1 und BRCA2 / Alexandra Angela Becker". Köln : Deutsche Zentralbibliothek für Medizin, 2013. http://d-nb.info/1045459046/34.
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MARGARESE, Naomi. "Genetic analysis of BRCA1 and BRCA2 genes in Sicilian high risk families and functional characterization of BRCA1 variants of uncertain significance (VUS)". Doctoral thesis, Università degli Studi di Palermo, 2014. http://hdl.handle.net/10447/90823.
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Oh, Yeum Mok, i Yeum Mok Oh. "BRCA1 and BRCA2 Gene Mutations in Colorectal Cancer: A Systematic Review and Meta-Analysis". Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625685.
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Background: The relevant risks associated with BRCA1 and BRCA2 mutation in breast and ovarian cancer have been well studied. BRCA mutations have also been found to be associated with other cancers, including colorectal cancer, but with conflicting results.
Aims: We performed a systematic review and meta-analysis to identify, characterize, and review published studies evaluating BRCA mutation carriers with colorectal cancer, and to quantify the risk of colorectal cancer overall and in subgroups of BRCA mutation carriers.
Methods: Eligible studies were retrieved through systematic review using multiple databases. Unadjusted odds ratios were used to derive pooled estimates of colorectal cancer risk overall and in subgroups defined by mutation type, comparison group, and study design.
Results: A total of 18 studies were included in the systematic review, of which 14 were also used in the meta-analysis: seven cohort studies comparing to the general population, five case-control studies, four cohort studies involving pedigree analysis, and two kin-cohort studies. Meta-analysis not differentiating between BRCA1 and BRCA2, revealed a statistically significant increased risk of colorectal cancer in BRCA mutation carriers in a fixed-effects model (OR=1.22, 95%CI=1.01-1.48, p=0.041), but not in a random-effects model (OR=1.20, 95%CI=0.96-1.50, p=0.111). Analyses stratified by study design and comparator found no association between BRCA mutation and colorectal cancer risk. In subgroup meta-analyses by BRCA type, BRCA1 mutation was associated with increased risk of colorectal cancer (OR=1.48, 95%CI=1.13-1.94, p=0.005), but not in BRCA2 mutation.
Conclusion: Systematic review and meta-analysis point at potential 1.22-fold greater risk of colorectal cancer in BRCA mutation carriers, attributable largely to a 1.48-fold greater risk of colorectal cancer in BRCA1 mutation carriers, regardless of age.
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Litman, Rachel. "Characterization of the BACH1 Helicase in the DNA Damage Response Pathway: a Dissertation". eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/329.
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DNA damage response pathways are a complicated network of proteins that function to remove and/or reverse DNA damage. Following genetic insult, a signal cascade is generated, which alerts the cell to the presence of damaged DNA. Once recognized, the damage is either removed or the damaged region is excised, and the original genetic sequence is restored. However, when these pathways are defective the cell is unable to effectively mediate the DNA damage response and the damage persists unrepaired. Thus, the proteins that maintain the DNA damage response pathway are critical in preserving genomic stability.
One essential DNA repair protein is the Breast Cancer Associated gene, BRCA1. BRCA1 is essential for mediating the DNA damage response, facilitating DNA damage repair, and activating key cell cycle checkpoints. Moreover, mutations in BRCA1 lead to a higher incidence of breast and ovarian cancer, highlighting the importance of BRCA1 as a tumor suppressor. In an effort to better understand how BRCA1 carried out these functions, researchers sought to identify additional BRCA1 interacting proteins. This led to the identification of several proteins including the BRCA1 Associated C-terminal Helicase, BACH1. Due to the direct interaction of BACH1 with a region of BRCA1 essential for DNA repair and tumor suppression, it was speculated that BACH1 may help support these BRCA1 function(s). In fact, initial genetic screenings confirmed that mutations in BACH1 correlated not only with hereditary breast cancer, but also with defects in DNA damage repair processes.
The initial correlation between BACH1 and cancer predisposition was further confirmed when mutations in BACH1 were identified in the cancer syndrome Fanconi anemia (FA) (complementation group FA-J), thus giving BACH1 its new name FANCJ. These findings supported a previously established link between the FA and BRCA pathways and between FA and DNA repair. In particular, we demonstrated that similar to other FA/BRCA proteins, suppression of FANCJ lead to a substantial decrease in homologous recombination and enhanced both the cellular sensitivity to DNA interstrand cross-linking agents and chromosomal instability. What remained unknown was specifically how FANCJ functioned and whether these functions were dependent on its interaction with BRCA1 or other associated partners. In fact, we identified that FANCJ interacted directly with the MMR protein MLH1. Moreover, we found that the FANCJ/BRCA1 interaction was not required to correct the cellular defects in FA-J cells, but rather that the FANCJ/MLH1 interaction was required. Although both the FA/BRCA and MMR pathways undoubtedly mediate the DNA damage response, there was no evidence to suggest that these pathways were linked, until recently. Our findings not only indicate a physical link between these pathways by protein-protein interaction, but also demonstrated a functional link.
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Novak, David. "A multifaceted approach to elucidating the role of BRCA1- and BRCA2- related genes in hereditary breast cancer". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86576.
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5-10% of hereditary breast cancer cases are caused by germline mutations in well-defined, dominantly acting susceptibility genes such as BRCA1 and BRCA2. However, more than 50% of the genetic predisposition to hereditary breast cancer remains unexplained. In the following thesis, we present a multifaceted approach aimed at further elucidating hereditary breast cancer associated with BRCA1 and BRCA2 interacting genes; specifically, by analyzing the potential contribution from of two previously unscreened BRCA1-associating genes, RAP80 and Abraxas, assessing the presence and risk associated with CHEK2 susceptibility alleles in the previously uninvestigated French Canadian population and by investigating molecular and cellular mechanisms underlying the increased risk associated with PALB2 susceptibility alleles.A combination of genotyping 96 BRCA1/2 negative, high risk breast cancer patients and segregation analysis was utilized in the determination of whether or not RAP80 and Abraxas are breast cancer susceptibility genes. The contribution of CHEK2 associated breast cancer amongst the French Canadian population was determined through the genotyping 25 BRCA1/2 negative, high risk breast cancer and a cohort of 25 controls. Finally, the biological significance of four PALB2 susceptibility alleles was investigated through the use of the cellular cytotoxicity assay WST-1, telomere specific Q-FISH, centromere specific FISH and spectral karyotyping.
The results presented herein suggest that both RAP80 and Abraxas are not high to moderately penetrant breast cancer susceptibility genes. Further, our results suggest that alleles other than the CHEK2 1100delC are unlikely to significantly contribute to the hereditary breast cancer risk in the French Canadian population. Lastly, the results obtained throughout our analysis of PALB2 heterozygous cell lines may be suggestive of a possible chromosomal instability phenotype predisposing carriers to additional tumourgenic mechanisms.
5-10% des cas de cancer héréditaire du sein sont causés par des mutations germinales dans des gènes des susceptibilité bien caractérisés et à l'effet dominant tel les gènes BRCA1 et BRCA2. Cependant, plus de 50% de la prédisposition génétique au cancer du sein héréditaire demeure inexpliquée. Dans cette thèse, nous présentons une approche à trois volets ayant pour but d'étudier les cas de cancer héréditaire du sein associés avec des gènes interagissant avec BRCA1 et BRCA2. D'abord, nous analysons la contribution potentielle de deux gènes peu caractérisés qui sont partenaires de BRCA1 : RAP80 et Abraxas. Nous étudions ensuite le risque associé avec la présence d'allèles nouveaux ou connus du gène CHEK2 jamais encore caractérisés dans la population canadienne française. Enfin, nous examinons les mécanismes cellulaires et moléculaires responsables de l'augmentation du risque de cancer du sein conférée par des allèles à risque du gène PALB2.
Nous avons utilisé une combinaison de génotypage chez 96 patients souffrant du cancer du sein mais étant non porteurs de mutations dans BRCA1/2 et d'analyse de ségrégation des mutations et des phénotypes dans leurs familles afin de déterminer si RAP80 et Abraxas sont ou non des gènes de prédisposition au cancer héréditaire du sein. La contribution au risque de cancer du sein du gène CHEK2 fût déterminée grâce au génotypage de 25 cas à haut risque, non porteurs de mutations chez BRCA1/2, et de 25 contrôles sans cancer. Finalement, nous avons étudié 4 allèles nonsense du gène PALB2 à l'aide du test de toxicité cellulaire WST-1 ainsi qu'en utilisant l'analyse Q-FISH spécifique aux télomères, l'analyse FISH spécifique aux centromères et finalement par caryotype spectral (SKY).
Les résultats présentés dans cet ouvrage suggèrent que RAP80 et Abraxas ne sont pas des gènes de susceptibilité au cancer du sein à pénétrance moyenne ou élevée. De plus, il est peu probable que des allèles du gène CHEK2 autres que l'allèle connu 1100delC contribuent de façon significative au risque de cancer du sein héréditaire dans la population canadienne française. Par contre, les résultats de notre analyse du gène PALB2 dans les lignées cellulaires hétérozygotes pour un allèle nonsense suggèrent la possibilité que la présence de ces allèles crée de l'instabilité chromosomique chez les porteurs de mutations qui puissent prédisposer à la progression tumorale.
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Santos, Catarina Gomes Rodrigues. "Avaliação da patogenicidade de mutações germinativas de significado desconhecido nos genes BRCA1 e BRCA2 em famílias portuguesas". Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/9163.
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Santos, Catarina Gomes Rodrigues. "Avaliação da patogenicidade de mutações germinativas de significado desconhecido nos genes BRCA1 e BRCA2 em famílias portuguesas". Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/9163.
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Ramos, Marcelo Cristiano de Azevedo. "Análise de custo-efetividade de programa para diagnóstico de mutação germinativa em genes BRCA1/2 e de estratégias preventivas para pacientes com câncer de ovário e seus familiares de primeiro grau". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-09052018-082903/.
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INTRODUÇÃO: Diversas sociedades profissionais recomendam a realização de testes genéticos para mulheres que desenvolveram câncer de ovário, a fim de identificar portadores de mutação germinativa em genes BRCA1/2 e oferecer terapia redutora de risco. OBJETIVO: O objetivo deste estudo foi realizar análise de custo-efetividade de programa para diagnóstico de mutação germinativa em genes BRCA1/2 e de estratégias preventivas para pacientes com o diagnóstico de câncer de ovário e seus familiares de primeiro grau. METODOLOGIA: O estudo realizou análise de custo-efetividade mediante desenvolvimento de modelo de decisão de Markov e perspectiva do Sistema Único de Saúde. As estratégias comparadas refletiram a adoção de teste genético e estratégias preventivas para pacientes e familiares ou o acompanhamento proposto atualmente. A razão de custo-efetividade incremental foi expressa em termos de custo por caso evitado de neoplasia maligna. A análise de sensibilidade foi realizada de forma determinística univariada. RESULTADOS: Demonstrou-se incremento em efetividade e em custos com a realização de testes genéticos e a adoção de medidas profiláticas para pacientes e familiares. A razão de custo-efetividade incremental foi calculada em R$ 14.224,40 e em R$ 908,58, respectivamente, por caso evitado em pacientes com o diagnóstico prévio de câncer de ovário e em seus familiares de primeiro grau. Estes valores foram considerados inferiores ao limiar de custo-efetividade selecionado no estudo (de R$ 7.543,50 a R$ 23.786,70). DISCUSSÃO: O programa analisado pode ser considerado como estratégia custo-efetiva para a realidade nacional, sobretudo no que tange aos familiares de primeiro grau de pacientes com o diagnóstico de câncer de ovário. Outras publicações demonstraram conclusões similares para o tema em diversos países. CONCLUSÃO: Um possível desdobramento deste trabalho poderia ser representado pela realização de uma análise de impacto orçamentário da incorporação do programa como política de saúde no paísINTRODUCTION: Several professional societies recommend performing genetic tests for women who have developed ovarian cancer in order to identify BRCA1/2 germline-mutation carriers and offer risk-reducing therapy. OBJECTIVE: The objective of this study was to perform a cost-effectiveness analysis of a BRCA1/2 germline mutation diagnosis program and preventive strategies for patients diagnosed with ovarian cancer and their first degree relatives. METHODS: The study performed a cost-effectiveness analysis through the development of a Markov decision model and the perspective of the Unified Health System. The compared strategies reflected the adoption of genetic testing and preventive strategies for patients and their relatives or the usual follow-up. The incremental cost-effectiveness ratio was expressed in terms of cost per avoided case of cancer. Sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: There has been an increase in effectiveness and in costs with genetic testing and the adoption of prophylactic measures for patients and their relatives. The incremental cost-effectiveness ratio was calculated at R$ 14,224.40 and R$ 908.58, respectively, for avoided cases in patients with prior diagnosis of ovarian cancer and their first-degree relatives. These values were considered lower than the cost-effectiveness threshold selected in the study (from R$ 7,543.50 to R$ 23,786.70). DISCUSSION: The analyzed program can be considered as a cost-effective strategy for the national reality, especially in relation to the first-degree relatives of patients with ovarian cancer. Other publications have shown similar conclusions for the subject in several countries. CONCLUSION: A possible development of this work could be represented by a budget impact analysis of the incorporation of the program as health policy in Brazil
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Palfner, Sonja. "Gen-Passagen molekularbiologische und medizinische Praktiken im Umgang mit Brustkrebs-Genen ; Wissen - Technologie - Diagnostik". Bielefeld Transcript, 2008. http://d-nb.info/994330804/04.
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Galvão, Violeta Regnier. "Biomarcadores na anafilaxia a platinas". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-27032018-133113/.
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INTRODUÇÃO: O câncer constitui-se na principal causa de mortalidade entre indivíduos de 45 a 84 anos, configurando-se em um dos principais problemas de saúde pública dos países em desenvolvimento. As reações de hipersensibilidade aos quimioterápicos têm aumentado, impedindo muitas vezes a utilização de terapias de primeira linha no tratamento de neoplasias primárias ou recidivantes. O procedimento de dessensibilização é uma abordagem alternativa, por meio do qual o paciente passa a tolerar a medicação que antes desencadeava reações potencialmente letais. Quimioterápicos do grupo das platinas são exemplos de drogas passíveis de readministração por meio do processo de dessensibilização, no entanto faltam biomarcadores preditivos de reações durante o procedimento. OBJETIVOS: O objetivo principal do estudo foi avaliar o papel do teste de ativação de basófilos (BAT) como biomarcador para reações de hipersensibilidade ocorridas durante a dessensibilização em pacientes alérgicas às platinas. Como objetivo secundário, avaliou-se a prevalência e o impacto da mutação dos genes BRCA 1 e 2 em pacientes com hipersensibilidade imediata à carboplatina submetidas à dessensibilização. MÉTODOS: Padronizou-se o BAT, com análise da expressão de CD63 e CD203c na superfície de basófilos de pacientes com hipersensibilidade imediata às platinas submetidas à dessensibilização. Foram realizados BATs em 15 pacientes portadoras de neoplasias malignas submetidas a 27 dessensibilizações devido à anafilaxia a quimioterápico do grupo das platinas e em 12 indivíduos de dois grupos controle (Grupo 1: seis pacientes tolerantes às platinas e Grupo 2: seis voluntários sadios que nunca foram expostos às platinas). Os resultados dos BATs foram comparados entre os três grupos. Correlacionou-se o BAT com a ocorrência ou não de reação durante a dessensibilização e com os níveis de triptase sérica. Para análise da prevalência e impacto da mutação dos genes BRCA 1 e 2 nas dessensibilizações, realizou-se análise retrospectiva de prontuários de 138 portadoras de neoplasias malignas ginecológicas submetidas à dessensibilização à carboplatina. RESULTADOS: O BAT foi positivo em 11 das 15 pacientes alérgicas (n= 11; 73,3%), com aumento de expressão de CD203c e CD63 em 11 (73,3%) e 6 (40%) pacientes, respectivamente. Todos os participantes dos grupos controles apresentaram testes negativos. Maior expressão de CD63 foi observada em pacientes com reações iniciais mais graves. O BAT foi positivo em 92,3% das reações ocorridas durante as dessensibilizações (n=12/13), sendo positivo em todas as reações que apresentaram aumento concomitante de triptase sérica (n=5). Com relação à mutação dos genes BRCA 1 e 2, sua prevalência foi de 34% nas pacientes com hipersensibilidade às platinas (n=47/138), sendo que 51% das portadoras reagiram durante a dessensibilização. CONCLUSÕES: O BAT positivo, com aumento da expressão de CD63 e/ou CD203c na superfície do basófilo, identificou pacientes alérgicos às platinas com especificidade de 100% e sensibilidade de 73,3%. O BAT e a mutação dos genes BRCA 1 e 2 identificaram pacientes mais propensos a reagir durante o procedimento de dessensibilização. A utilização de biomarcadores preditores de reações durante a dessensibilização aos quimioterápicos do grupo das platinas pode aumentar a segurança do procedimento e auxiliar na manutenção do esquema quimioterápico de primeira linha do pacienteINTRODUCTION: Cancer is the leading cause of death in the age group of 45 to 84 years, and one of the main public health issues in developing nations. Hypersensitivity reactions to chemotherapeutic agents have been increasing, sometimes hindering the use of first-line therapies in the treatment of primary or relapsed tumors. Rapid drug desensitization (RDD) is an alternative approach, through which a patient becomes tolerant to the medication that once triggered a potentially lethal hypersensitivity reaction. Platinum-based compounds are examples of drugs that can be readministered through the desensitization procedure, but currently there are no known biomarkers that could help predict reactions during RDD. OBJECTIVES: The main goal of our study was to assess the basophil activation test (BAT) as a biomarker of breakthrough reactions occurred during RDD in patients allergic to platinum-based agents. As a secondary goal, we evaluated the prevalence and impact of the BRCA 1/2 mutation in carboplatin-allergic patients undergoing RDD. METHODS: We standardized the BAT by evaluating CD63 and CD203c expressions on the basophils of patients with immediate hypersensitivity reactions to platinum-based agents undergoing RDD. We analyzed BATs of 15 patients with malignant neoplasms who had undergone 27 RDD procedures due to anaphylaxis to platinum-based agents, and of 12 control subjects (Group 1: six patients tolerant to platinum-based agents, and Group 2: six healthy volunteers who had never been exposed to platinum-based agents). BAT results were compared among the three groups. We correlated BAT results with the occurrence of breakthrough reactions during RDD and with serum tryptase levels. To conduct the analysis of the BRCA 1/2 mutation prevalence and its impact on RDD, a retrospective review of 138 medical records of patients with gynecological malignancies who underwent RDD to carboplatin was performed. RESULTS: BAT was positive in 11/15 allergic patients (73.3%), with increased expression of CD203c and CD63 in 11 (73.3%) and 6 (40%) patients, respectively. All control subjects presented negative BATs. A higher CD63 expression was observed in patients with severe initial reactions. BAT was positive in 92.3% of the breakthrough reactions occurred during RDD (n=12/13), and in all reactions with concomitant increased tryptase levels (n=5). Regarding the BRCA1/2 mutation, its prevalence was 34% in patients allergic to platinum-based agents (n=47/138), and 51% of the mutation carriers had breakthrough reactions during RDD. CONCLUSIONS: A positive BAT, with an increased expression of CD63 and/or CD203c, identified patients allergic to platinum-based agents with a specificity of 100% and a sensitivity of 73.3%. The BAT and the BRCA 1/2 mutation helped identify patients at risk of breakthrough reactions during RDD. The use of predictive biomarkers of breakthrough reactions during RDD to platinum-based agents might enhance RDD safety and help maintain a patient`s first-line treatment
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Gedminaitė, Jurgita. "Krūties vėžiu sergančių moterų BRCA1, BRCA2, CHEK2 ir NBS1 genų mutacijų tyrimas ir jų ryšio su kitais prognoziniais veiksniais paieška". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130919_143947-94587.
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Apie 5–10 proc. visų krūties navikų atvejų sudaro paveldimas vėžys. BRCA1 ir BRCA2 genai yra patys svarbiausi polinkį susirgti krūties vėžiu sąlygojantys genai. Kiti reikšmingai su padidėjusia krūties navikų išsivystymo rizika susiję – CHEK2 ir NBS1 genai. Šiame darbe ištirtos paveldimos dažniausiai Europos regione nustatomos šių genų mutacijos. Nustatytas BRCA1 ir CHEK2 genų mutacijų dažnis tarp jaunų krūties vėžiu susirgusių moterų, ištyrinėtos jų sąsajos su pacientės amžiumi, naviko klinikinėmis ir morfologinėmis savybėmis. Išanalizuota šeiminės anamnezės prognozinė vertė nustatant paveldimus BRCA1 ir CHEK2 genų pokyčius. Pirmą kartą Lietuvoje įsisavintas CHEK2 bei NBS1 genų tyrimas, nustatyta, kokios CHEK2 geno mutacijos dažniausios. Nors NBS1 geno mutacijų nerasta, bet įsisavinta metodika, kuri bus panaudota ateities tyrimams. Sukurtas kompleksinis BRCA1 bei CHEK2 genų mutacijų radimo prognozavimo modelis. Šiandien klinikinėje praktikoje panašūs modeliai naudojami įvertinti BRCA1/2 genų mutacijų tikimybę. Jų pritaikomumas ir specifiškumas skirtingose etninėse grupėse gali skirtis. Naudojant tirtų pacienčių charakteristikas, įtraukiant ne tik šeiminę anamnezę, pacientės ypatybes, bet ir klinikinius bei molekulinius navikų požymius, sukurti mūsų regionui pritaikyti modeliai bei nustatyti kriterijai, kurie padės atrinkti pacientes genetiniam konsultavimui dėl BRCA1 bei CHEK2 genų mutacijų. Šis naujas požiūris turi didžiulę praktinę naudą.Approximately 5–10% of all breast cancer cases are considered to be hereditary. BRCA1 and BRCA2 genes are the most important breast cancer predisposing genes. Other genes significantly linked with an increased risk of breast tumors are CHEK2 and NBS1 gene. In this scientific work were studied the most prevalent in European region mutations of these genes. The rate of BRCA1 and CHEK2 gene mutations in young women with breast cancer was evaluated and the relationships between these mutations and patient's age, clinical and morphological tumor features are examined. The prognostic value of family history was analyzed when forecasting hereditary BRCA1 and CHEK2 gene mutations. For the first time in Lithuania the CHEK2, NBS1 genes tests were applied and the evaluation of which CHEK2 gene mutations are most prevalent was obtained. Although NBS1 gene mutations were not found, but applied test technique will be used in future research. There was created a prognostic model for determination of BRCA1 and CHEK2 gene mutations. In today's clinical practice similar models are used to assess the likelihood of the BRCA1/2 mutation. Their applicability and specificity in different ethnic groups may vary. Applying the studied data there was created a model adapted to our region. Testing patients, there were considered not only family medical history and personal characteristics, but also the clinical and molecular features of tumors. The criteria have been found which will help in selecting... [to full text]
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Marafie, Makia. "Investigations of BRCA1 or BRCA2 gene changes in women affected by early onset breast or ovarian cancer". Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311839.
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Padilla, Sirera Natàlia. "Novel approaches for in silico identification of pathogenic variants in BRCA1 and BRCA2 hereditary breast and ovarian cancer predisposition genes". Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670705.
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Variants germinals a les proteïnes BRCA1 i BRCA2 poden alterar la funció protectora d’aquestes a l’ADN, incrementant el risc de desenvolupar càncer de mama i ovari hereditari (HBOC). Identificació d’aquells individus portadors de variants patogèniques permet canalitzar-los en programes específics de prevenció i vigilància, augmentant les seves taxes de supervivència. Per això, en primer lloc, cal identificar quines de les variants són patogèniques. Malauradament, no sempre hi ha prou informació per arribar a una conclusió. En aquesta situació, els predictors de patogenicitat dissenyats per estimar computacionalment el dany causat per les variants poden proporcionar una valuosa informació.
En aquest treball presentem una nova família de predictors de patogenicitat per BRCA1 i BRCA2. Aquests predictors difereixen en el seu objectiu: un està entrenat per estimar l’impacte molecular de les variants sobre la funció HDR de BRCA1 i BRCA2, i l’altre està entrenat per estimar la significació clínica d’una variant, és a dir, si la seva classificació és patogènica o neutra. Els seus rendiments han estat provats i són comparables als d’altres mètodes àmpliament utilitzats en el camp. Addicionalment, vam presentar els predictors al repte ENIGMA de la 5a Avaluació Crítica de la Interpretació del Genoma (CAGI), trobant que els nostres mètodes, especialment aquells que estimen l’impacte funcional de les variants, es classifiquen en les primeres posicions en comparació amb les altres eines.
Per tal de difondre aquesta família de predictors a la comunitat científica, hem construït el lloc web BRASS (https://www.biotoclin.org/BRASS), on els usuaris poden analitzar les seves variants de BRCA1 i BRCA2 amb canvi de sentit. Els usuaris més avançats també poden interpretar les prediccions mitjançant una mètrica de fiabilitat i diversos gràfics contextualitzant la seva puntuació amb la d’un conjunt de variants curades manualment.
Independentment, hem aplicat els nostres coneixements sobre predictors de patogenicitat en un gran projecte internacional per caracteritzar un nou trastorn neurològic pediàtric causat per variants patogèniques a la histona H3.3. Vam combinar l’ús de predictors de patogenicitat estàndard amb evidències d’anàlisis estructurals i càlculs biofísics per proporcionar una visió mecanicista de l’impacte de les variants causals.Variantes germinales en las proteínas BRCA1 y BRCA2 pueden alterar la función protectora de estas en el ADN, incrementando el riesgo de desarrollar cáncer de mama y ovario hereditario (HBOC). Identificación de aquellos individuos portadores de variantes patogénicas permite canalizarlos hacia programas específicos de prevención y vigilancia, aumentando sus tasas de supervivencia. Para ello, en primer lugar, es necesario identificar cuáles de las variantes son patogénicas. Desafortunadamente, no siempre hay suficiente información para llegar a una conclusión. En esta situación, los predictores de patogenicidad diseñados para estimar computacionalmente el daño causado por las variantes pueden proporcionar una valiosa información. En este trabajo presentamos una nueva familia de predictores de patogenicidad para BRCA1 y BRCA2. Estos predictores difieren en su objetivo: uno está entrenado para estimar el impacto molecular de las variantes en la función HDR de BRCA1 y BRCA2, y el otro está entrenado para estimar la significancia clínica de una variante, es decir, si su clasificación es patogénica o neutra. Sus rendimientos han sido probados y son comparables a los de los métodos ampliamente utilizados en el campo. Además, presentamos los predictores al desafío ENIGMA de la 5ª Evaluación Crítica de la Interpretación del Genoma (CAGI), encontrando que nuestros métodos, especialmente aquellos que estiman el impacto funcional de las variantes, se clasifican en las primeras posiciones en comparación con las otras herramientas. Para difundir esta familia de predictores a la comunidad científica, hemos construido el sitio web BRASS (https://www.biotoclin.org/BRASS), donde los usuarios pueden analizar sus variantes de BRCA1 y BRCA2 con cambio de sentido. Los usuarios más avanzados también pueden interpretar las predicciones utilizando una métrica de confiabilidad y varios gráficos que contextualizan su puntuación a la de un conjunto de variantes seleccionadas manualmente. De forma independiente, aplicamos nuestro conocimiento sobre los predictores de patogenicidad en un gran proyecto internacional para caracterizar un nuevo trastorno neurológico pediátrico causado por variantes patogénicas en la histona H3.3. Combinamos el uso de predictores patogénicos estándar con evidencia de análisis estructurales y cálculos biofísicos para proporcionar una visión mecanicista del impacto de las variantes causales.
Germline variants in BRCA1 and BRCA2 can disrupt the DNA protective role of these proteins resulting in an increased risk of developing hereditary breast and ovarian cancer (HBOC). Identification of those individuals carrying pathogenic variants will allow channeling them into specific programs of prevention and surveillance, incrementing their survival rates. For this purpose, first, it is necessary to identify which of the variants are pathogenic. Unfortunately, there is not always enough information to reach a conclusion. In this situation, pathogenicity predictors designed to computationally estimate the damage caused by variants, can provide valuable information. Here, we present a novel family of pathogenicity predictors for BRCA1 and BRCA2. These predictors differ in their objective: one is trained to estimate the molecular impact of variants on the HDR function of BRCA1 and BRCA2, and the other is trained to estimate the clinical significance of a variant, that is, whether it should be classified as pathogenic or neutral. Their performances have been tested and are comparable to those of widely used predictors in the field. Additionally, we presented them to the ENIGMA challenge from the 5th Critical Assessment of Genome Interpretation (CAGI), finding that our predictors, especially those estimating the functional impact of variants, ranked in the top positions compared to other tools. In order to disseminate this family of predictors to the scientific community, we have built the BRASS website (https://www.biotoclin.org/BRASS), where users can analyze their missense BRCA1 and BRCA2 variants. More advanced users can also interpret the predictions using a reliability metric and several plots contextualizing the score to that of a set of manually curated variants. Independently, we applied our knowledge about pathogenicity predictors in a large international effort to characterize a novel pediatric neurologic disorder caused by pathogenic variants in histone H3.3. We combined the use of standard pathogenic predictors with evidence from structural analyses and biophysical computations to provide a mechanistic view of the impact of the causative variants.
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Reilly, Drew D. "The Narratives of Young Women with BRCA 1/2 Gene Mutation: A Qualitative Analysis". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1910.
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A narrative qualitative research design was used to understand the stories of young women diagnosed with BRCA1 and BRCA 2 genetic mutation. Four participants were selected who met the following criteria: (a) the participant is diagnosed with BRCA1 or BRCA2 genetic mutation, b) is within the age range of 18 to 35, (c) is without a cancer diagnosis, and is (d) not currently pregnant and does not have children. The four participants were interviewed through open-ended inquiry. The participants’ narratives proved both similar and dissimilar. The themes were organized into within-case narratives and across-case narratives. The narratives revealed that young BRCA previvors face unique challenges and experiences, and many can be viewed from an underlying feminist lens. In response to the research questions, BRCA previvors revealed detailed narratives, explored issues of family planning, and explained the ways in which BRCA has changed their worldviews.
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Dufloth, Rozany Mucha. "Carcinoma de mama hereditario em mulheres brasileiras : mutações dos genes BRCA1 e BRCA2, polimorfismos dos genes de reparo do DNA e caracterização imunoistoquimica pela tecnica de Tissue Microarray". [s.n.], 2004. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313286.
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Orientadores: Luiz Carlos Zeferino, Fernando Carlos de Lander SchmittTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-04T01:21:30Z (GMT). No. of bitstreams: 1 Dufloth_RozanyMucha_D.pdf: 623963 bytes, checksum: 756d732465da74e705449411420fb717 (MD5) Previous issue date: 2004
Resumo: OBJETIVOS: Identificar mutações nos genes BRCA1 e BRCA2 em uma população brasileira com câncer de mama hereditário; analisar a freqüência de polimorfismos nos genes XRCC1, XPD, XRCC3 e RAD51 em um grupo de pacientes brasileiras e sua associação com a susceptibilidade ao câncer de mama; analisar expressão das proteínas p63, CK5 e P-caderina em cânceres de mama familiar e esporádico. MÉTODOS: Este estudo teve componentes do tipo transversal e do tipo caso-controle. Foram constituídos quatro grupos: pacientes com câncer hereditário de mama; pacientes com câncer de mama esporádico; mulheres sem câncer de mama e com história familiar positiva de câncer de mama e/ou ovário; mulheres sem câncer de mama e sem história familiar de câncer de mama e/ou ovário. Foram coletados 10ml de sangue periférico para a realização de técnicas moleculares, nomeadamente Single Strand Conformation Polymorphism (SSCP) e Seqüenciação Direta. Espécimes de câncer de mama, conservados em blocos de parafina, foram selecionados no Laboratório de Patologia do Hospital das Clínicas/Unicamp, Brasil e no Laboratório de Patologia do Hospital São João/Universidade do Porto, Portugal, totalizando 168 casos. Dos blocos doadores foram extraídos cilindros de 2mm de diâmetro e depositados nos blocos de parafina receptores, usando Tissue Microarrayer (Beecher Instrumensts, Silver Spring, Maryland). Nestes cortes foi feita a pesquisa dos marcadores de diferenciação do fenótipo basal/mioepitelial. RESULTADOS: Foram identificadas quatro mutações (13%), sendo uma mutação no gene BRCA1 e três no gene BRCA2. No BRCA1 foi encontrada uma mutação do tipo frameshift. Duas mutações do BRCA2 são tipo nonsense e a outra do tipo unclassified variant. Não houve associação estatisticamente significante entre os alelos e genótipos dos polimorfismos dos genes de reparo do DNA, XRCC1, XPD, XRCC3 e RAD51. O câncer de mama familiar mostrou diferenças estatisticamente significantes do fenótipo imunoistoquímico dos marcadores de células basais/mioepiteliais (P-caderina, p63 and CK5), em relação aos cânceres esporádicos. CONCLUSÃO: Foram identificadas uma mutação no gene BRCA1 e três mutações no gene BRCA2 em mulheres com câncer de mama e história familiar de câncer de mama, o que correspondeu a uma freqüência de 13% (4/31). Não foi observada associação da susceptibilidade ao câncer de mama com os polimorfismos dos genes XRCC1, XPD, XRCC3 e RAD51 em um grupo de pacientes brasileiras. Os marcadores p63, CK5 e P-caderina foram mais freqüentemente expressos no câncer de mama familiar. A melhor caracterização do câncer familiar como entidade biológica distinta do câncer esporádico pode ser uma ferramenta útil para selecionar mulheres que deveriam submeter-se ao rastreamento de mutações nos genes BRCA1 e BRCA2
Abstract: OBJECTIVE: To identify mutations in BRCA1 and BRCA2 genes in a Brazilian population of women with hereditary breast cancer; to analyze the frequency of polymorphism in genes XRCC1, XPD, XRCC3 e RAD51 in a group of Brazilian patients and its association with breast cancer susceptibility; to analyze the expression of p63, CK5 and P-cadherin proteins in familial and sporadic breast cancers. METHODS: This study was in part transversal and in part crosssectional. The population evaluated in this study comprised four groups of women: patients with sporadic and familial breast cancers, women without breast cancer but with family history, women without breast cancer and without family history. The last group was the control group of this study. From each subject, 10ml of peripheral blood were collected to perform molecular analysis, namely Single Strand Conformation Polymorphism (SSCP) and Direct Sequencing. Paraffin blocks from breast cancer specimens were selected from the Pathology Laboratories from the Hospital das Clínicas/UNICAMP, Brazil and Hospital São João/Universidade do Porto, Portugal, totalising 168 cases. Cylinders with 2mm diameter were extracted from the donnor blocks using the Tissue Microarrayer technique (Beecher Instruments, Silver Spring, Maryland), and were sampled together to construct the receptor paraffin blocks. The analysis of mioepithelial differentiation/histogenesis was performed in these sections. Results analysis was carried out through the Chi-square test. RESULTS: Four mutations were identified: one in BRCA1 and three in BRCA2. A frameshift BRCA1 mutation, two nonsense BRCA2 and one unclassified variant BRCA2 mutation were identified. No statistically significant association between the alleles and genotypes DNA, XRCC1, XPD, XRCC3 and RAD51 polymorphism. Familial breast cancer was statistically different from sporadic cancer in regards of immunohistochemical phenotypes for basal/mioepithelial cell markers (Pcadherin, p63 and CK5). CONCLUSIONS: Thirteen percent of women with breast cancer and family history of breast cancer had at least one BRCA1 gene mutation and three BRCA2 gene mutations. We do not observe any statistical significance difference in the frequency of alleles and genotype of the genes XRCC1, XRCC3, XPD e RAD51 in the group of patients studied. The markers, CK5 e P-cadherin was more frequently in familial breast cancers. The characterization of familial breast cancer as a biological entity distinct from sporadic cancer might be a useful tool to select women that should be screened to BRCA1 and BRCA2 genes mutation triaging
Doutorado
Ciencias Biomedicas
Doutor em Tocoginecologia
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Larochelle, Chantal. "Interactions physiques et fonctionnelles entre la region C-terminale de la protéine BRCA1 et la kinase CDK7". Sherbrooke : Université de Sherbrooke, 2004.
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Gonzalez, Rachel Marie. "Reduced BRCA1 expression in breast and ovarian tumorigenesis /". Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/6334.
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Kotian, Shweta. "Identification of Novel Genes in BRCA1-Regulated Pathways". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366341897.
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Jansson, Sandra, i Lisa Candell. "Ett liv i förändring - att bära på mutation i BRCA 1- eller BRCA 2-genen: en skildring av kvinnors upplevelser : En litteraturöversikt". Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-396781.
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Bakgrund: Mutation i BRCA-generna innebär kraftigt ökad risk att utveckla bröst- och ovarialcancer. Vetskap om att bära på denna genmutation innebär påfrestningar och psykosociala förändringar hos individen. Sjuksköterskor behöver insikt i hur detta tillstånd påverkar individen för att kunna tillfredsställa vårdbehovet på ett personcentrerat sätt. Syfte: Skildra kvinnors upplevelse av att bära på mutation i gen BRCA 1 eller BRCA 2. Metod: Allmän litteraturstudie med deskriptiv design. Resultatet baserades på tio originalartiklar med kvalitativ ansats från databaserna PubMed och Cinahl. Resultat: Upplevelsen varierade mellan kvinnor, och känslomönster identifierades mellan individer i liknande livssituationer. Många uppgav en initial känsla av chock, samt känslor av osäkerhet kring den upplevda hälsan. De beskrev ett informationsbehov och en upplevd brist på kunskap hos vårdgivaren. Detta resulterade i rädsla att bli vilseledd samt känslor av ensamhet, tomhet och isolering. Undersökningsgruppen beskrev en oro och rädsla inför en eventuell framtida cancerdiagnos och hur detta skulle komma att påverka dem och deras familj. De beskrev även att denna vetskap tvingade dem in i en beslutsprocess gällande framtida livshändelser, såsom profylaktisk kirurgi och familjeplanering. Slutsats: Kvinnorna upplevde mycket oro, ångest, rädsla och osäkerhet inför framtiden. De upplevde ett informationsbehov som inte tillfredsställdes samt ett stort behov av stöd. Vårdpersonalen behöver mer kunskap om hur vetskapen om genmutation i BRCA 1 eller BRCA 2 kan påverka patienten. Strategier behöver utformas för att tillfredsställa kvinnornas behov av stöd och information. Detta i syfte att främja hälsa lindra lidande.Background: Mutation in the BRCA genes involves a significantly increased risk of developing breast- and ovarian cancer. Knowledge about carrying this gene mutation lead to stress and resulted in psychosocial changes. Nurses needs insight into how this situation affects the individual in order to satisfy the care needs with a person-centered approach. Purpose: The aim of the study was to investigate and depict women’s experience of carrying a mutation in the BRCA 1 or BRCA 2 gene. Method: General literature review with descriptive design. Results was based on ten qualitative original research articles from the databases PubMed and Cinahl. Results: The experience varied woman to women, and emotional patterns were identified between individuals in similar life situations. Many expressed an initial feeling of shock, and uncertainty about the perceived health. They described a need for information, and experienced a lack of knowledge among the caregivers, which resulted in fear of being misled. The study group described feelings of fear and worry for a future cancer diagnosis and how that would affect their families and themselves. They also described that it forced them into a decision making process regarding risk reducing surgery and family planning. Conclusion: These women experienced great levels of worry, anxiety, fear and uncertainty regarding the future. They experienced a need for information that was not satisfied, and also a great need for support. Caregivers need more knowledge about how awareness of gene mutation in BRCA 1 or BRCA 2 can affect the patient. Strategies need to be designed to meet women´s need of information and support. This in order to promote health and ease suffering.
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Puget, Nadine. "Prédisposition génétique au cancer du sein : recherche de mutations dans les régions régulatrices et de réarrangements structuraux du gène BRCA1". Lyon 1, 1999. http://www.theses.fr/1999LYO1T093.
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Payne, Shannon Renée. "Analysis of BRCA1 genomic structure : novel germline mutations and somatic alterations in breast cancer /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10295.
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Yassaee, Vahid Reza. "Towards a general strategy for breast cancer : investigation of germline mutations of BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer". Thesis, University of Sheffield, 2002. http://etheses.whiterose.ac.uk/5987/.
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Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. It results from genetic and environmental factors leading to the accumulation of mutations in essential genes, BRCA 1and BRCA2. To date, germline mutations in the BRCAI and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. This study was set for two main purposes, in first for a cohort study of selected population (Iranian women) with early-onset breast cancer and secondly to evaluate and improve upon existing mutation detection techniques with respect to the BRCA genes. With the collaboration of two main centres for cancer research and treatment in Tehran-Iran, clinical information, family history and peripheral blood were obtained from 96 unrelated families for scanning of germline mutations in the BRCA 1 and BRCA2 genes. These sets of samples consists of 104 women under the age of forty-five, 88 patients affected with early-onset breast cancer or ovarian cancer and 16 unaffected individuals with strong family history of breast and/or ovary cancer. BRCA1 exons 11 and BRCA2 exons 10 and 11 by the Protein Truncation Test (PTT) and BRCAI exons 2, 3, 5, 13 and 20 and BRCA2 exons 9, 17,18 and 23 with the Single Strand Conformation Polymorphism (SSCP)assay were analysed on genomic DNA amplified by polymerase chain reaction. Ten sequence variants were identified: five are frame shift (putative mutations-four novel); three missense changes of unknown significant and two polymorphisms, one seen [BRCA2 (IVSI6-14T>C)] commonly in both Iranian and British population. Identification of these novel mutations suggests that any given population should develop a mutation database for its breast cancer screening. The pattern of mutations seen in the BRCA genes does not appear to differ from other populations studied. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 250/0 in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective. To address the penetrance and mutation spectrum of germline mutation of the contributed genes within Iranian population further studies should be performed. Meta-PCR technique was evaluated for its implication of BRCA genes scanning. Three distinct sets of BRCA gene fragments were selected to assemble with different approach for downstream analysis: the first set consisted ofBReA1 exons 2, 20 and BRCA2 exon 18 and their subsequent analysis by Protein Truncation Test; the second set comprised BRCAI exons 2, 20, 23 and 24 and their subsequent analysis by direct sequencing; and the last one contained six key coding regions from the BRCA genes, the 5' and 3'termini of exon 11 from both BRCAI and BRCA2 genes and exons 2 and 20 from BRCAI. Downstream analysis of Meta-PCR products by Protein Truncation Test was used rather than direct nucleotide sequencing because the total assembled above fragments size (~2.8kb) is sufficiently big to ignore analysing by the latter approach. PTT and direct sequencing were chosen because of their high sensitivity and specificity. These three trials were performed successfully suggesting that it may be possible to assemble the entire of coding regions of BRCAI and BRCA2 genes in a multi-step procedure.